CN1578626A - 多泡乳液局部给药系统 - Google Patents
多泡乳液局部给药系统 Download PDFInfo
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Abstract
本发明揭示了一种多泡乳液与药学/药理学活性剂合用的局部给药组合物。多泡乳液由季铵盐乳化剂如behentrimoninm methosulfate所形成。乳剂是多层片状,是油和水相的一系列同心球或泡,可在显微镜下看到。结果,活性物质于一段时间内持续释放,而非如一般局部用剂的峰释放。
Description
技术领域
本发明涉及具有独特多泡乳液特性的局部用组合物。
技术背景
当然,局部给药系统是已知的,它们利用从固体到润滑度各异的各种乳霜、到油膏及洗液的物理特性。局部给药系统的成功关键是他们在传送所谓“活性物质(active)”时有多成功。例如:大多数局部用活性物质在刚施用时有很高或所谓“峰”释放,之后随着时间的过去而大量减少。这是令人不满意的,因为初始峰剂量太高而缺乏经时的持续性,结果是效力减少。再者,不只是缺乏持续性和峰释放的监察是一问题,而且峰释放时给药部位剂量过多而可能引起皮肤刺激。
容易受到峰剂量及皮肤刺激影响的局部用产品可有多种物理形态,包括固体,液体,悬浮液,半固体(如:乳霜、凝胶体、乳液、糊剂或“粘着剂”),粉末或微细分散液体如喷雾剂或薄雾。局部用产品的例子一般分类为“化妆品”,(包括润肤霜和润肤液等护肤品)和“治疗化妆品”,如磨砂膏和/或皮肤细胞更新剂;香料,如香水及古龙水,及除臭剂;剃须有关产品,如乳霜、“保护带(Bracers)”及剃须后润肤水;脱毛剂及其它脱毛产品;皮肤清洁剂、收缩水及收敛剂、预湿布及面巾;防晒和遮光剂;沐浴产品,如油;眼部护理产品,如眼霜及去妆剂;脚部护理产品,如粉末及喷雾剂;皮肤着色剂及化妆产品,如粉底,腮红,眼影及线,唇彩及睫毛膏;唇膏及口红;头发护理及治疗产品,如洗头水、护发素、着色剂、染发剂、漂白剂、直发剂、及持久曲发产品;婴儿产品,如婴儿乳液、油、洗头水、粉及湿巾;女性用品,如除臭剂及冲洗液;皮肤科医生或化妆师使用的皮肤或面部皮片;及其它。
局部用产品的例子一般归类为“局部活性剂”:是很多及各式各样的,包括非处方(over-the-counter)和/或处方产品,如:止汗药、驱虫剂、遮光剂及晒伤治疗剂、除粉刺剂、抗生素、治疗性维生素A、去头屑剂、外用止痛剂(如辣椒辣素产品)、外用避孕用品、局部给药系统、栓剂及灌肠剂、痔疮治疗剂、阴道治疗剂、糖锭、及具有治疗或其它作用的很多其它产品。其它局部用产品包括手、面、身体肥皂和清洁剂及其它形式的皮肤清洁剂,以及家用清洁剂及很多其它家庭用品,如:溶剂、推进剂,磨光剂、滑润剂、粘合剂、蜡及其它局部施用于人体或在正常使用中与人体局部接触的产品。
本发明对局部用化妆品,局部用治疗化妆品及局部活性剂是有用的。
因此,本发明的主要目的是提供含有药学/药理学活性剂的局部给药组合物,它没有常见的峰释放问题也没有失效持续释放问题。
重要的是,本发明也涉及制备局部给药组合物的方法,该方法保证含有药学/药理活性剂的乳剂是一多泡乳液。
实现上述目的及其它目的的方法及方式在以后本发明详述中将会明了。
发明概述
本发明涉及制备局部给药组合物的方法及组合物本身。组合物的特征是一多泡乳液,它可含有药学/药理活性剂。如果在本说明书描述的方法中使用乳化剂,它能提供多泡乳液,最好为季铵盐如behentrimonium methosulfate,用量为组合物总重量的0.1%到30%。较佳为组合物总重量的0.5%到5%。在本方法中,药学/药理活性剂是以最可兼容的状态混合(油状或水状),其后将它与季铵盐乳化剂完全充分地混合。另外,药学/药理活性剂可被悬浮于乳剂中,包裹在泡内。这样就形成了避免峰释放而长久持续释放的多泡乳液。组合物本身惊人地影响皮肤的生物物理特性,如增加血流量,减少水份经皮流失,及增加皮肤水合作用。
附图说明
图1显示一抗真菌药从传统乳剂和本发明的多泡乳液释放速度的比较。
图2显示本发明对外围血流量的改变。
图3显示本发明对经皮水份流失的改变。
图4显示本发明对皮肤保湿动力学十二小时的改变。
图5显示本发明对皮肤保湿水平两周的改变。
具体实施方式
本组合物是一局部给药组合物,它的特征是一多泡乳液,可含有药学/药理活性剂。
一般而言,此组合物包括阳离子活化季铵盐乳剂,其脂肪链长度为C12到C30,较佳为C19到C26,最佳为C22,形成在油/水乳液系统中的多泡乳液。理想的乳化剂是由菜子(油菜籽)油得来的季铵盐,其芥酸含量很高。此物质将称为behentrimonium methosulfate,它一般与十八烷醇(cetearyl alcohol)合用,behentrimonium methosulfate在第二乳化剂(如十八醇)中的重量比为25%。Croda公司是已知的behentrimonium methosulfate的供货商,以IncroquatBehenyl TMS的商标出售。产品以商标IncroquatBehenyl TMS出售的详情在Croda公司1994年6月1日的小册子内有描述,将在IDS中提交专利局。该小册子中描述了此组合物是一流的阳离子乳剂能加强护肤霜的野外使用特性及赋予头发不缠绕的特性。1994年6月1日的小册子内没有透露使用IncroquatBehenyl TMS来制作多泡乳液,如本说明书所述。
本说明书所用的短语“多泡乳液”是指两相的油/水乳液系统,具有多层系列油和水相的同心球体或壳体。它相当地不同于由内相悬浮于紧接的外相的液滴所组成的胶束乳液系统,也不同于由悬浮于紧接的外相的一个个油和水的胶束。多泡乳液的层可用显微镜看到,很易与小泡的别种层分别出来。于显微镜下它看似洋葱的横切面。结果是,活性截留于交替的油相或交替的水相或存于小泡内,可以定时释放而非峰释放(传统液滴乳液的常见特性)。
为要得到多泡乳液,需要使用正确的乳化剂及以正确的方法制备产品。两者均在本说明书中加以描述。
季铵盐较佳为behentrimonium methosulfate,该乳化剂的量为组合物总重量的0.1%到30%,较佳为组合物总重量的0.5%到5%。
如之前所述,理想的乳化剂可购自Croda公司。山萮基四价表面活性剂较佳为behentrimonium methosulfate或behentrimonium chloride。behentrimoniummethosulfate的理想来源是INCROQUATBehenyl TMS(来自Croda公司),含有25%的behentrimonium methosulfate。
或者,表面活性剂可以是behentrimonium chloride,dibehenyldimoniummethosulfate或behenamidopropyl ethyldimonium ethosulfate。Croda公司提供的形式是季铵盐乳化剂,由behentrimoniaum methosulfate和十八烷醇合起来组成,使用方便,是behentrimonium25%,十八烷醇75%的锭剂。较佳的是,它与例如由Croda公司提供的脂肪醇第二乳化剂一起使用。较理想的是乳化剂为十八醇。第二乳化剂的量应为behentrimonium sulfate的1.5倍到4倍。
该乳化剂系统可用以在油和水中及油/水乳液中形成多泡乳液,虽然前者较为常见。
用于本发明的局部给药组合物的确切局部活性剂是什么并不重要。事实上,无论水溶性和/或油溶性药学/药理活性剂均可使用。制剂领域的技术熟练人士会知道不同的活性剂的精确百分比随活性剂而异,事实是,一般来说活性剂在0.01%到15%的范围内。典型的活性剂可以是痤疮活性剂包括红斑痤疮治疗剂、止痛剂、麻醉剂、肛门直肠药、抗组胺药、抗炎药、抗生素、抗真菌药、抗病毒药、抗微生物剂,如:银、银化合物、磷酸克林霉素、红霉素、磺胺醋酰钠、灭疥螨药、灭虱药、抗肿瘤药、止汗药、止痒剂、抗孢子剂、抗皮脂溢剂、灼伤活性剂、烧灼剂、脱色剂、尿布疹治疗剂、酶、头发生长活性剂、角质溶解剂、口溃疡活性剂、感冒疮活性剂、牙齿活性剂、唾液活性剂、光敏作用活性剂、类固醇、晒伤活性剂、遮光剂、疣活性剂、伤口治疗产品、灭滴灵、及视黄醇。
除活性剂和多泡乳液乳化剂到季铵盐及behentrimonium methosulfate之外,此组合物可含有其它赋形剂为特定产品领域提供不同形式的产品。
本发明的局部制剂,可制成多种物理形态。主要产品形态是固体、乳霜、乳液、及凝胶/清液。这些形态的主要区分是它们的物理外观及粘性(或粘稠度),主要由乳化剂和浓度调节剂的存在及数量所控制,事实上在很多情况下,主要成分是这些产品形态中常见的。此外,特定的局部制剂通常可制成这些不同形态。固体一般是稳固及不可倾倒的,常制成棒或棍形或特别的形态;固体可以是不透明的或透明的,可选择性地含有溶剂(包括水及酒精)、乳化剂、增湿剂、软化剂、香料、染料/着色剂、防腐剂及活性成分。乳霜及乳液常常是相似的,主要是粘度的区别(乳霜比乳液较浓及粘);乳霜和乳液可以是不透明的、透明的或清澈的,一般含有乳化剂、溶剂(包括水及酒精)及粘性调节剂。乳霜及乳液也可选择性地含有增湿剂及软化剂(特别是护肤品)、以及香料、染料/着色剂、防腐剂及活性成分。凝胶/清液可在一定的粘度范围内制备,由稠(高粘度)到薄(低粘度),与乳霜及乳液的主要区别是凝胶/清液多数是清澈而不是不透明的。与乳霜及乳液相似,凝胶/清液可含有乳化剂、溶剂(包括水及酒精)及粘性调节剂、也可含有增湿剂及软化剂、香料、染料、防腐剂及活性成分。
用于本发明制剂的适当的粘度调节剂(也就是增浓及稀释剂),包括(但不限于)保护胶体或非离子树脂如羟乙基纤维素(例如:Cellosize HEC QP52,000-H,由Amerchol生产)、黄原胶、菌核胶(Amigel 1.0)、及硅酸铝镁(VeegumUltra)、硅石、微晶蜡、蜂蜡、石蜡、及鲸蜡醇十六酸酯。另外,按照本发明可合用这些粘度调剂或用其混合物。本发明制剂中所用的一种特别好的增稠剂,特别在凝胶/清液的情况下,是非离子聚合物羟乙基纤维素,它与硝酸锶兼容,在pH值3左右是稳定的。
本发明制剂中适用的溶剂包括(但不限于)水、乙醇、丁二醇、丙二醇、异丙醇、异戊二烯二醇、丙三醇、聚乙二醇200、聚乙二醇400、聚乙二醇600、及聚乙二醇800。另外,根据本发明,可合用这些溶剂,或用它们的混合物。
本发明制剂中适用的表面活性剂包括(但不限于)非离子表面活性剂,如表面活性剂190(聚二甲基硅氧烷共聚醇)、聚山梨酸酯20(Tween 20)、聚山梨酸酯40(Tween 40)、聚山梨酸酯60(Tween 60)、聚山梨酸酯80(Tween 80)、月桂酰胺DEA、可卡酰胺(cocamide)DEA、及可卡酰胺MEA;两性表面活性剂,如oleyl betaine and cocamidopropyl betaine(Velvetex BK-35);及阳离子表面活性剂,如磷脂PTC(Cocamidopropyl phosphatidyl PG-dimonium chloride)。按照本发明可合用这些表面活性剂或用它们的混合物。阴离子表面活性剂在单独用于含二偶氮利定脲、羟苯甲酸甲酯和对羟苯甲酸丙酯高浓度锶盐的制剂中时存在稳定性问题。
本发明制剂中适用的防腐剂包括(但不限于)抗微生物剂,如:Germaben II(由ICI生产;丙二醇、二偶氮利定脲、羟苯甲酸甲酯和对羟苯甲酸丙酯)、羟苯甲酸甲酯、对羟苯甲酸丙酯、咪唑烷基脲、苯甲醇、山梨酸、安息香酸、苯甲酸钠、二氯苄醇和甲醛,以及物理稳定剂和抗氧化剂,如:生育酚(维生素E)、抗坏血酸钠/抗坏血酸、棕榈酸抗坏血酸酯及五倍子酸丙酯。另外,本发明的制剂中也可合用这些防腐剂或用它们的混合物。
本发明制剂中适用的增湿剂包括(但不限于)乳酸和其它羟基酸及它们的盐、丙三醇、丙二醇、丁二醇、PCA钠、聚乙二醇200、聚乙二醇400、及聚乙二醇800。本发明制剂中适用的软化剂包括(但不限于)PPG-15硬脂醚、羊毛脂醇、羊毛脂、羊毛脂衍生物、胆固醇、矿脂、新戊醇十八烷酯、硬脂酸辛酯、矿物油、硬脂酸异十六烷酯、Ceraphyl 424(肉豆蔻酸十四酯)、辛基十二醇、二甲硅油(Dow Corning 200-100 cps)、苯基聚三甲基硅氧烷(Dow Corning 556)、Dow Corning 1401(环甲基硅酮和聚二甲基硅氧烷醇)、及环甲基硅酮(DowCorning 344)、及Miglyol 840(由Huls所生产;二辛酸丙二醇酯)。另外,按照本发明可适当地合用增湿剂及缓和软化剂及用其混合物。
本发明的制剂中可用适当的香料及色素,如:FD&C Red No.40及FD&CYellow No.5。适用于局部用产品的香味及色素的其它例子是本领域已知的。
本发明制剂中其它合适的添加物及附加成分包括(但不限于)研磨剂、吸收剂、抗粘结剂、防泡沫剂、防静电剂、收敛剂(例如:金缕梅、酒精、及草药提取物,如:甘菊精)、粘合剂/赋形剂、缓冲剂、螯合剂(例如:依地烯EDTA)、成膜剂、调节剂、不透明剂、pH调节剂(例如:柠檬酸及氢氧化钠)、及防护剂。这些成分的例子,及适合于局部用产品配方中的其它例子,可见于化妆品及用具、香料协会(CTFA)的出版物。例如:CTFA Cosmetic Ingredient Handbook,第二版John A.Wenninger and G.N.McEwen,Jr编着。(CTFA,1992)。
得益于本发明的多泡乳液系统的例子及其各自不同的流变性能如下所述。
配方例
温和的清洁剂
氢化可的松软膏
水 77.33% 凡士林 30%
CMT-30 4.0% 羊毛脂醇 3%
Incromectant LAMEA 5.0% 矿油 10%
羟苯甲酸甲酯 0.1% 地蜡 5%
黥蜡醇1 3.0% Incroquat Behenyl TMS 2%
十八烷醇 0.5% 丙二醇 3%
Incroquat Behenyl TMS 5.0% 氢化可的松 1%
丙二醇 5.0% 水 41%
羟苯甲酸丙酯 0.05% Methyl Gluceth 20 4%
羟苯甲酸丁酯 0.02% 苯氧基乙醇 1%
防晒乳 神经酰胺乳
Incroquat Behenyl TMS 3% 芝麻油 4%
黥蜡醇 13% Incroquat Behenyl TMS 4%
十八烷醇 1% 黥蜡醇 3%
肉桂酸辛酯 7.5% 十八烷醇 1%
水杨酸辛酯 5% 澳洲坚果油 1%
澳洲坚果油 1% Cetiol LC 2%
鳄梨油 1% 鳄梨素 2%
芝麻油 4% Crodamol OHS 3%
二丙酮3 4% 神经酰胺II 0.2%
水 66.2% 水 71.5%
甘油 4% 丁二醇 4%
Liquid Germall Plus 0.3% Liquid Germall Plus 0.3%
桃仁提取物 1%
Rovisome ACE 3%
海洋植物乳
抗生素喷雾乳
芝麻油 4% 芝麻油 5%
Incroquat Behenyl TMS 4% Incroquat Behenyl TMS 3%
黥蜡醇 13% 黥蜡醇 12%
十八烷醇 1% 十八烷醇 0.5%
澳洲坚果油 1% Cetiol LC 2%
Cetiol LC 2% 水 83.56%
鳄梨素 2% 甘油 3%
Crodamol OHS 3% 多粘菌素B 0.14%
水 64.7% 硫酸新霉素 0.8%
丁二醇 4%
Liquid Germall Plus 0.3%
桃仁提取物 1%
Rovisome ACE 3%
Oceagen 3%
Dermasaccharides GY 2%
Dermasaccharides SEA 2%
硅氧烷喷流
氧化锌喷流
水 90.7% 水 73.7%
Incroquat Behenyl TMS 2% Incroquat Behnyl TMS 2%
聚二甲基硅氧烷 2% 聚二甲基硅氧烷 2%
环二甲基硅酮 5% 环二甲基硅酮 5%
Liquid Germall Plus 0.3% Finsolv TN 5%
氧化锌 12%
Liquid Germall Plus 0.3%
剃须后润肤香脂/调理剂
自晒黑乳
水 75.5% Incroquat Behenyl TMS 3%
EnHance 0.5% 黥蜡醇 3%
甘油 3% 十八烷醇 1%
Incroquat Behenyl TMS 3% 芝麻油 5%
聚二甲基硅氧烷 1% Schercemol SHS 3%
环二甲基硅酮 5% 羟苯甲酸丙酯 0.05%
黥蜡醇 1.5% 水 45.55%
醇 SD-40 10% 甘油 4%
Liquid Germall Plus 0.5% 羟苯甲酸甲酯 0.8%
Sun Caps 903 27.6%
DHA 4%
赤藓酮糖 3%
AHA乳霜w/防晒霜
尿布疹乳霜
水 63.5% Vegelatum Equiline 17.5%
丁二醇 3% 羊毛脂醇 1.5%
甘油 3% 蜂蜡 2.5%
Incroquat Behenyl TMS 3% 石蜡 2.5%
黥蜡醇 12% Incroquat Behenyl TMS 2.5%
十八烷醇 1.5% 芝麻油 3%
Labrafil M2130 2% 葵花油 3%
Parsol 1789 3% 水 61.4%
芝麻油 4% 硼酸 0.1%
Crodamol OHS 2% Oatmeal 1%
甲氧基肉桂酸辛酯 5% 氧化锌 4%
乙醇酸 7.5% 苯氧基乙醇 1%
Liquid Germall Plus 0.5%
喷雾乳
喷雾w/氧化可的松
水 81.5% 水 80.5%
甘油 4% 甘油 4%
黥蜡醇 3% 黥蜡醇 3%
Incroquat Behenyl TMS 3.5% Incroquat Behenyl TMS 3.5%
十八烷醇 1% 十八烷醇 1%
芝麻油 4% 芝麻油 4%
Crodamol OHS 2.5% Crodamol OHS 2.5%
Liquid Germall Plus 0.5% 氧化可的松 1%
Liquid Germall Plus 0.5%
霜粉 霜粉w/咪康唑
水 42.5% 水 40.5%
聚二甲基硅氧烷 1% 咪康唑 2%
Incroquat Behenyl TMS 2.5% 聚二甲基硅氧烷 1%
环二甲基硅酮 9% 环二甲基硅酮 9%
Finsolv TN 5% Incroquat Behenyl TMS 2.5%
Tapioca Pure 14% Finsolv TN 5%
Dry Flo Elite 10% Tapioca Pure 14%
金缕梅 15% Dry Flo Elite LL 10%
苯氧基乙醇 1% 金缕梅 15%
苯氧基乙醇 1%
以上的每一配方中,共同特征是使用IncroquatBehenyl TMS。
如前所述,本发明不仅是选择适当的乳化剂以形成多泡乳液,而且也是以特别的方法制备以确保多泡乳液的形成。依照本方法,活性物质与其同相的其它所有兼容性成分混合。兼容性成分是指那些可溶于其中的。例如:如活性物质可溶于水,它即是乳液系统的水相。另一方面,如活性物质可溶于油,但不溶于水,它可与系统的油相混合。混合后,将活性物质及系统的其余部分,即基质,再与多泡乳化剂(如:behentrimonium methosulfate)高剪切混合直至肉眼观察显示已得到多泡乳液。典型地,这要在混合器(如:涡轮型螺旋桨混合器或cowles溶解器)中进行五到三十分钟。
提供以下实施例可进一步描述(而非限制)本发明。
实施例1
用本发明的多泡乳液制备产品。特别是,药物活性剂是已知的抗真菌药硝酸益康唑的1重量%混悬液。它是用包括3.5重量%IncroquatBehenyl TMS(25重量%behentrimonium methosulfate及75重量%cetearyl alcohol)的本发明的多泡乳液系统制备的。将该多泡乳液系统与葵花油、鲸蜡醇、十八烷醇、羟基硬脂酸辛酯、水、甘油及1重量%的硝酸益康唑抗真菌药混合。在高剪切混合后检查以确定形成多泡乳液后,系统外观为乳霜。
它在此测试中与一已知市售产品Johnson & Johnson的益康唑产品(Spectazole)相同药物的油/水乳剂)作比较。两者也是于一扩散室中作测试。扩散测试的结果显示本发明的多泡乳液是在一段时间内持续释放,而Spectazole则于短时间内峰释放。图1显示使用本发明制剂硝酸益康唑与市售Spectazole产品的释放速度数据。
实施例2
对实施例1相同的乳剂系统(减去活性)进行研究,以研究产品施用于皮肤时增加外周血流量的可能性。对十个健康的对象进行研究。将设定数量的产品施用于测试对象的面颊部。用激光多普勒测量法评估基线血流量。施用后的三到六小时后,结果显示本发明产品与基线相比有显著的血流量增加。应注意是,外周血流量的增加相当于较好的新陈代谢、细胞营养的增加、氧的增加及更快的细胞清除,血流量的增加对治疗及细胞更新是必需的。此测试证明多泡系统与基线产品相比可增加血流量。图2显示血流量数据。
实施例3
本实施例测量使用本发明时的经皮水份流失。这是评估皮肤保护屏障功效的重要方法。经皮水份流失的增加是皮肤保护屏障受损的信号。临床的情形,各种各样的皮炎或外在的因素,如:溶剂、清洁剂及其它刺激物均增加经皮水份的流失。好的局部用产品不应刺激皮肤。它们应增强皮肤的功能、维持皮肤的健康及帮助修补受损的皮肤屏障。本实施例中,用经本发明多泡乳液治疗和未经治疗的揭带皮肤的恢复速率作评价。
详细情形是,二十个健康的志愿者参加这次研究。测量表皮水份流失的基线后,将皮肤反复贴胶带、揭胶带(二十次)直到表皮水份流失达到某个选定的值。将多泡乳液施用于一位置,对于治疗及未治疗的皮肤区域作表皮水份流失的测量,再得到数据。
结果显示于图3。显示经皮水份流失明显减少。详细情形是,以多泡乳液治疗过的区域恢复速度明显快于未治疗区域。
实施例4
对本发明的多泡乳液的实时及长期增湿效果进行研究。该系统在实施例1中已被描述。本实验中,评估了十二小时皮肤水合作用的增加两周内的长期效果。结果显示在一次使用的十二小时内(图4)及每天使用两次的两周内(图5)皮肤水合作用明显增加。即使在末次使用的二十四小时后,皮肤湿度也明显增加,表明有长时效应。
从以上研究及特别是从图1至图5,可以看到本发明的多泡乳液系统可避免峰释放,事实上,有持续释放的特征(图1)。与局部施用相关区域的外周血流量也增加(图2),经皮水份流失减少(图3),由皮肤湿度改变证明系统的作用是持久的(图4及图5,六小时及两周)。因此,可以看到本系统能达到至少所有设定的目标。
由以上描述可以看到,本发明能达到至少所有设定的目标。
Claims (27)
1.局部给药组合物,包含衍生自季铵盐乳化剂的多泡乳液。
2.如权利要求1所述的组合物,其中,多泡乳液衍生自脂肪碳链长度为C12至C30的季铵盐乳化剂。
3.如权利要求2所述的组合物,其中,多泡乳液衍生自脂肪碳链长度为C19至C26的季铵盐乳化剂。
4.如权利要求3所述的组合物,其中,季铵盐乳化剂是长度为C22的脂肪碳链behentrimoninm methosulfate。
5.如权利要求4所述的组合物,其中,季铵盐乳化剂的量是组合物总重量的0.1%至30%。
6.如权利要求5所述的组合物,其中,季铵盐乳化剂的量是组合物总重量的约0.5%至5%。
7.如权利要求6所述的组合物,其中,季铵盐乳化剂是与脂肪醇第二乳化剂合用的。
8.如权利要求7所述的组合物,其中,脂肪醇第二乳化剂是十八烷醇(cetearylalcohol)。
9.如权利要求8所述的组合物,其中第二乳化剂的量是behentrimoninm sulfate的1.5倍至4倍。
10.如权利要求1所述的组合物,所述组合物包含活性物质,其中,药学/药理学活性剂是位于油泡内。
11.如权利要求1所述的局部给药组合物,所述组合物包含活性物质,其中,药学/药理学活性剂是位于水泡内。
12.如权利要求1所述的局部给药组合物,所述组合物包含一活性物质,其中,药学/药理学活性剂是包裹在泡内的。
13.如权利要求1所述的组合物,所述组合物包括赋形剂粉末。
14.如权利要求13所述的组合物,其中,赋形剂粉末选自滑石和玉米淀粉。
15.如权利要求14所述的组合物,其中,赋形剂粉末是滑石。
16.如权利要求1所述的组合物,其中,包含次要配合剂。
17.如权利要求16所述的组合物,其中,次要配合剂选自防腐剂、软化剂、保湿剂、乳液稳定剂、防水剂、护肤剂、调节剂及香料。
18.如权利要求1所述的局部给药组合物,其中,组合物的给药形式选自乳液、乳霜、可喷射的乳霜、及乳霜粉末制剂。
19.如权利要求1所述的组合物,所述组合物是半固体乳霜。
20.如权利要求1所述的组合物,所述组合物含有活性物质,其中,药学/药理学活性剂选自包括红斑痤疮治疗剂、止痛剂、麻醉剂、肛门直肠药、抗组胺药、抗炎药、抗生素、抗真菌药、抗病毒药、抗微生物剂,如:银、银化合物、磷酸克林霉素、红霉素、磺胺醋酰钠、灭疥螨药、灭虱药、抗肿瘤药、止汗药、止痒剂、抗孢子剂、抗皮脂溢剂、灼伤活性剂、烧灼剂、脱色剂、尿布疹治疗剂、孢子、头发生长活性剂、角质溶解剂、口溃疡活性剂、感冒疮活性剂、牙齿活性剂、唾液活性剂、光敏作用活性剂、类固醇、晒伤活性剂、遮光剂、疣活性剂、伤口治疗产品、灭滴灵、及视黄醇。
21.制备包含多泡乳剂和药学/药理学活性剂的局部给药组合物的方法,所述方法包括:将活性物质与油相或水相可混溶的基质混合,所述基质取决于活性物质;将活性物质和基质与占组合物总重量0.5%至5%的季铵盐乳化剂混合,直至形成能按时释放活性物质的多泡乳液。
22.如权利要求21所述的方法,其中,季铵盐乳化剂的量是组合物总重量的0.1%至30%。
23.如权利要求21所述的方法,其中,季铵盐乳化剂的量是组合物总重量的0.5%至5%。
24.如权利要求21所述的方法,其中,季铵盐乳化剂具有长度为C12至C30的脂肪碳链。
25.如权利要求21所述的方法,其中,季铵盐乳化剂具有长度为C19至C26的脂肪碳链。
26.如权利要求21所述的方法,其中,季铵盐乳化剂具有长度为C22的脂肪碳链。
27.如权利要求21所述的方法,其中季铵盐乳化剂是behentrimoninmmethosulfate。
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US09/944,760 | 2001-08-31 | ||
US09/944,760 US6709663B2 (en) | 2001-08-31 | 2001-08-31 | Multivesicular emulsion drug delivery systems |
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CN1578626A true CN1578626A (zh) | 2005-02-09 |
CN100404019C CN100404019C (zh) | 2008-07-23 |
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US (1) | US6709663B2 (zh) |
EP (1) | EP1420645B1 (zh) |
JP (1) | JP4252899B2 (zh) |
KR (1) | KR100615116B1 (zh) |
CN (1) | CN100404019C (zh) |
AT (1) | ATE447392T1 (zh) |
AU (1) | AU2002320238B2 (zh) |
BR (1) | BRPI0212116B8 (zh) |
CA (1) | CA2457852C (zh) |
DE (1) | DE60234260D1 (zh) |
DK (1) | DK1420645T3 (zh) |
ES (1) | ES2336083T3 (zh) |
HK (1) | HK1065921A1 (zh) |
MX (1) | MXPA04001885A (zh) |
PT (1) | PT1420645E (zh) |
WO (1) | WO2003020037A1 (zh) |
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EP1420645A4 (en) | 2006-09-06 |
KR20040044512A (ko) | 2004-05-28 |
US20030049281A1 (en) | 2003-03-13 |
JP4252899B2 (ja) | 2009-04-08 |
BR0212116A (pt) | 2004-07-20 |
PT1420645E (pt) | 2010-02-04 |
KR100615116B1 (ko) | 2006-08-22 |
CN100404019C (zh) | 2008-07-23 |
CA2457852C (en) | 2006-06-06 |
ES2336083T3 (es) | 2010-04-08 |
EP1420645A1 (en) | 2004-05-26 |
US6709663B2 (en) | 2004-03-23 |
BRPI0212116B8 (pt) | 2021-05-25 |
WO2003020037A1 (en) | 2003-03-13 |
EP1420645B1 (en) | 2009-11-04 |
MXPA04001885A (es) | 2005-04-19 |
CA2457852A1 (en) | 2003-03-13 |
DE60234260D1 (de) | 2009-12-17 |
AU2002320238B2 (en) | 2005-02-17 |
JP2005501877A (ja) | 2005-01-20 |
DK1420645T3 (da) | 2010-03-15 |
ATE447392T1 (de) | 2009-11-15 |
HK1065921A1 (en) | 2005-03-11 |
BRPI0212116B1 (pt) | 2016-01-19 |
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